Tuberculosis

Notes

Definition & classification

Tuberculosis (TB) is one of the worlds most deadly infective diseases. It is caused by mycobacterium, a genus of actinobacteria.

In the UK TB has an incidence of around 1 in 10,000. This is significantly higher in London where incidence is 3.5 in 10,000.

Multi-drug resistant TB (MDR-TB) poses a significant health risk, in the UK, the rate of MDR-TB has doubled in a decade. This is being combated with multiple-drug regimens and directly observed therapy.

It is thought that 1/3 of the world's population are infected with TB though the majority of these are not active infections. The WHO estimated that 9 million people developed TB in 2013 and that 1.5 million died from TB of whom 25% were co-infected with HIV. Mycobacterium tuberculosis is the second most common infectious cause of death in adults (HIV is first). Significant strides have been made in the prevention and treatment of TB, between 1990 and 2013 mortality from TB has dropped by 45%.

Mycobacterium

TB is caused by mycobacterium and spread via respiratory droplets.

Mycobacterium are an aerobic bacteria, those capable of causing TB in humans are referred to as the mycobacterium complex (MTb).

The most commonly discussed organisms are Mycobacterium tuberculosis and Mycobacterium bovis. Other members of the MTb include Mycobacterium africanum and Mycobacterium microti.

Mycobacterium are:

Obligate aerobes: that is mycobacterium require oxygen to grow.

Facultative intracellular: can grow outside the cell but find it advantageous to be intracellular.

Acid fast bacilli (AFB): refers to a resistance to decolourisation of staining by acid.

Natural history

TB has a complex natural history.

Once mycobacterium bacilli have been inhaled patients may follow a number of clinical paths:

Immediate clearance

Primary TB: the initial infection, often subclinical, suppressed in the majority of individuals.

Primary-progressive TB: primary infection is not suppressed, almost always pulmonary in nature.

Latent TB: the outcome in the majority of patients with Primary TB. Non-infectious state.

Post-primary TB: also termed reactivation TB. It occurs in patients with latent TB, frequently due to immunocompromise (e.g. AIDs). May be pulmonary (55%) or extra-pulmonary (45%).

Inhaled bacilli find their way into alveoli, here they begin dividing. This initial infection is termed primary TB. Once a critical mass is reached a host immune response is elicited. The highly antigenic mycobacterium produces a strong immune response. Alveolar macrophages phagocytose bacilli which continue to proliferate.

The Ghon complex, a pathognomonic lesion most commonly seen in children, may develop. The complex has three components:

Ghon focus (a small caseating granuloma)

Lymphadenitis

Lymphangitis

After 2-10 weeks a sufficient cell-mediated response halts the proliferation of the bacilli in the majority of individuals. These patients develop latent TB. They may have a Ranke complex - a healed Ghon’s complex. Patients with latent TB may go on to develop reactivation with post-primary TB.

A small proportion of patients (around 5%) will develop primary-progressive TB, this is almost always pulmonary in nature. Primary-progressive TB has a number of manifestations:

Miliary TB (haematogenous spread of TB)

Primary caseous pneumonia

Tuberculous bronchopneumonia

Clinical features

Active TB is frequently asymptomatic, when symptomatic fever, weight loss and cough are most commonly seen.

Active TB may be primary-progressive or post-primary TB. The features of TB are dependent on the organ system involved with the lungs most frequently affected. Post-primary TB may be pulmonary (55%) or extra-pulmonary (45%). Primary-progressive disease almost always manifests itself with pulmonary disease.

Pulmonary TB

Pulmonary TB is the most common clinical manifestation of TB. It may be asymptomatic or present with the classic triad of:

Cough

Fever

Weight loss

Shortness of breath and haemoptysis can also be present. Additional symptoms may be seen with laryngeal and pleural involvement.

Diagnosis of latent TB

Mantoux test

This is the first line test in the diagnosis of latent TB. It Involves an intradermal injection of tuberculin, a purified protein derivative from M. tuberculosis.

If a patient has had exposure to TB they exhibit a delayed (type IV) hypersensitivity reaction. Diagnosis is based on the degree of the local epidermal reaction.

Previous BCG vaccination affects results. Interpretation is somewhat variable and at times the results inconclusive. The Mantoux test is also used prior to the administration of the BCG vaccine.

Interferon gamma release assay

These assays detect the bodies cellular immune response to TB. It tests for the T-cell interferon gamma response to M. tuberculosis antigens.

Its indications are complex, typically used after a positive Mantoux.

It is unaffected by previous BCG and non-tuberculous mycobacterium (NTM).

Diagnosis of active TB

Active TB is diagnosed with microbial tests.

Stains and Cultures

Three early morning sputum samples are taken on consecutive days. These are sent for acid-fast bacilli (AFB) smear and culture.

The smear is stained with auramine O which has largely replaced Ziehl-Neelsen staining. A negative smear result does not exclude TB. Around 30% of positive cultures will have negative staining.

Culture, utilising a medium such as Lowenstein-Jensen, is a highly specific test. However, it does take 4-6 weeks to get results.

Polymerase chain reaction (PCR)​

DNA PCR is a nucleic acid amplification technique. It allows for rapid and accurate testing.

It is an expensive test and is not currently part of NICE recommend investigations for standard practice.

Imaging & biopsies

When active pulmonary TB is suspected we obtain a chest radiograph and CT to look for effusion, cavitation, infiltrates and lymphadenopathy.

When active extrapulmonary TB is suspected we must rule out pulmonary disease with a chest radiograph and CT. Imaging of suspected affected area should be obtained. Consider biopsy if applicable e.g. lymph node.

In miliary TB consider the need for a lumbar puncture and CT/MRI head.

Bacille Calmette-Guérin

The BCG is the worlds most utilised vaccine with an estimated 3 billion vaccinations administered.

Mantoux test

A Mantoux test (tuberculin skin test) is required prior to administration in those aged > 6 years, or younger if there is a history of exposure to TB.

A positive result contraindicates the vaccine due to the risk of a severe reaction. It does not indicate the patient is immune to TB.

BCG

BCG is a live attenuated vaccine. Its efficacy is dependent on a number of factors, particularly age: it is more effective when administered at a younger age.

It is also protective against leprosy (caused by a NTM) and is a treatment in bladder cancer.

Antibiotics

A number of antibiotics ('RIPE') may be used to treat TB.

Rifampicin (R): stains secretions pink and may affect LFTs. It is an inducer of CYP450.

Isoniazid (H): side effects include polyneuropathy but these are rare at normal doses. It is an inhibitor of CYP450.

Pyrazinamide (Z): may cause hepatotoxicity. It is potently antiuricosuric and may cause gout.

Pericardial TB

In adults a starting dose of 60mg/day of prednisolone is standard. This may be tapered down after 2-3 weeks.

Meningeal TB

Meningeal TB is treated with rifampicin and isoniazid for 12 months whilst pyrazinamide and ethambutol are given for 2 months (2HRZE, 10HR).

In addition to the above antibiotics, glucocorticoids are initiated. In adults a starting dose, 20-40mg if on rifampicin or 10-20mg if not, of prednisolone is standard. This may be tapered down after 2-3 weeks.

Directly observed therapy

DOT involves direct supervision of patients during treatment for TB. It is thought to improve engagement and adherence with therapy.

Certain groups are thought to find greater benefit from DOT, these include alcoholics, homeless people and those with a history of poor adherence.